Interstitial fluid pressure was measured in normally hydrated rats during acute interstitial volume depletion by intravenous hyperoncotic bovine serum albumin infusion. Body fluid volumes, systemic arterial and venous pressure and selected blood and urine variables were also measured. The infusion increased plasma volume twice as much as do iso-oncotic infusions which cause comparable increases in mean central venous pressure. The kidneys responded with a diuresis and natriuresis closely resembling those which follow iso-oncotic infusion in normally hydrated rats. At the end of the elevated renal response plasma volume and plasma protein concentration were not restored to pre-infusion values; total interstitial fluid volume was decreased to one half its control value. Interstitial fluid pressure decreased linearly with volume so that effective interstitial compliance was constant at 0.0717 ml/mm Hg per gram dry tissue weight (1.79 ml/mm Hg per 100 g BW). This was not significantly different from the value 0.0704 previously found in normally hydrated rats but very significantly higher than that in dehydrated rats with comparable interstitial depletion. It is concluded that interstitial compliance is normal over a wide range of interstitial fluid volume in normally hydrated rats but that it can be altered in states of chronic body water depletion.